CA2050049A1 - Nor-statine and nor-cyclostatine polypeptides in the treatment of ocular hypertension and glaucoma - Google Patents
Nor-statine and nor-cyclostatine polypeptides in the treatment of ocular hypertension and glaucomaInfo
- Publication number
- CA2050049A1 CA2050049A1 CA002050049A CA2050049A CA2050049A1 CA 2050049 A1 CA2050049 A1 CA 2050049A1 CA 002050049 A CA002050049 A CA 002050049A CA 2050049 A CA2050049 A CA 2050049A CA 2050049 A1 CA2050049 A1 CA 2050049A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- composition
- phenyl
- morpholino
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 31
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- -1 (substituted)amino Chemical group 0.000 claims abstract description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 24
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 12
- 206010030043 Ocular hypertension Diseases 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 23
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 239000000126 substance Chemical group 0.000 claims description 9
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229910052739 hydrogen Chemical group 0.000 claims description 6
- 239000001257 hydrogen Chemical group 0.000 claims description 6
- 239000002674 ointment Substances 0.000 claims description 6
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 239000007900 aqueous suspension Substances 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- 230000001603 reducing effect Effects 0.000 claims description 4
- 239000003981 vehicle Substances 0.000 claims description 4
- 125000006531 (C2-C5) alkyl group Chemical group 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006532 (C3-C5) alkyl group Chemical group 0.000 claims description 2
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims description 2
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 2
- 125000006595 (C1-C3) alkylsulfinyl group Chemical group 0.000 claims 1
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 229940093470 ethylene Drugs 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- GZLMFCWSEKVVGO-UHFFFAOYSA-N 3-azaniumyl-2-hydroxy-5-methylhexanoate Chemical compound CC(C)CC(N)C(O)C(O)=O GZLMFCWSEKVVGO-UHFFFAOYSA-N 0.000 abstract description 4
- 229920001184 polypeptide Polymers 0.000 abstract description 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 2
- 229910052736 halogen Chemical group 0.000 abstract 1
- 150000002367 halogens Chemical group 0.000 abstract 1
- 238000000034 method Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000006194 liquid suspension Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- XXVORBRDDFTJEI-UHFFFAOYSA-N 2-hydroxy-1-[2-(4-oxopiperidin-1-yl)-1-piperazin-1-yl-2-piperidin-1-ylethenyl]piperidin-4-one Chemical group OC1N(CCC(C1)=O)C(=C(N1CCC(CC1)=O)N1CCCCC1)N1CCNCC1 XXVORBRDDFTJEI-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical class OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005237 alkyleneamino group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/553—Renin inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Abstract of the Disclosure A pharmaceutical composition for treating glaucoma or ocular hypertension is disclosed. The composition contains a nor-statine or nor-cyclostatine polypeptide of the formula:
or II
(wherein Z is R1-(Y)m-(A)p [in which R1 is alkyl, alkoxy, (substituted)amino, Y is CO, P(O)(OCH3) or SO2; A is N(CH3), NH
or O, m and n are each 0 or l];
M is (substituted)phenyl, naphthyl, thienyl or benzyl;
Q is methyl or halogen;
R2 is (substituted)alkyl;
W is substituted methylene;
Z1 is CH2OH or R-U-T [in which R is CO, U is O, NH, NCH3, CH2 or a bond, and T is H, (substituted)alkyl, cycloalkyl, phenyl, or substituted amino];
L is CH or N;
R5 is imidazol-4-ylmethyl or alkyl; and R6 is alkoxy or alkylamino).
or II
(wherein Z is R1-(Y)m-(A)p [in which R1 is alkyl, alkoxy, (substituted)amino, Y is CO, P(O)(OCH3) or SO2; A is N(CH3), NH
or O, m and n are each 0 or l];
M is (substituted)phenyl, naphthyl, thienyl or benzyl;
Q is methyl or halogen;
R2 is (substituted)alkyl;
W is substituted methylene;
Z1 is CH2OH or R-U-T [in which R is CO, U is O, NH, NCH3, CH2 or a bond, and T is H, (substituted)alkyl, cycloalkyl, phenyl, or substituted amino];
L is CH or N;
R5 is imidazol-4-ylmethyl or alkyl; and R6 is alkoxy or alkylamino).
Description
~ 5 NOR-STATINE AND NOR-CYCLOSTATINE POLYREPTIDES IN THE
v TREATMENT OF OCULAR HYPERTENSION AND GLAUCOMA
0 1ie ~ ~f th~ Irve~tion The present invention relates to a method of treating patients suffering from glaucoma or ocular hypertension using nor-statine and nor-cyclostatine polypeptides.
B kqround of the Invention Glaucoma is a disease which ePfects the lives of many people. This eye disorder is caused by an increase in intraocular pressure, also known as ocular hypertension or glaucoma. Chronic glaucoma manifests itself through a gradual and progressive los~ of visual fields. Without treatment, such condition ultimately results in blindness.
Treatment has typically involved the topical application of agonists or antagonists of autonomic neuroeffectors, such as pilocarpine or timolol, or the systematic administration of carbonic anhydrase inhibitors. Failure of such topical methods leaves surgery as the only alternative. As a result, newer and safer drugs causing fewer side effects are constantly being investigated~
The compounds used in the present invention are known to have a renin inhibitory effect and thus be useful in treating certain forms of hypertension and congestive heart failure as disclosed in United States Patent Nos. 4,814,342 and 4,935,405. W. J. Giardina, et al, Pharmacol., 31, 124 30 (1989); H. H. 5tein, et al, Pharmacol., 31, 124 (1989); and European Patent Publication No. 0364804 refer to the use of certain renin-inhibitory compounds in the treatment of glaucoma.
Summary of the Invention The present invention relates to a method for treating glaucoma or ocular hypertension comprising administering an effective intraocular hypertension reducing amount of at least one compound of the formula ~2--Z ~C / y ~ N~
0 ~2 and ~13 N C 1~ C O R 6 H ll = H g Rs OH
or a pharmaceutically acceptable salt thereof, wherein Z is Rl-(Y)m-(A3p, where Rl is (Cl-C6)alkyl, amino, (Cl-C4)alkoxy, (Cl-C4)alkylamino, (Cl-C3)alkoxy (C2 C4) alkylenPamino~
15 CarbOXy(Cl-C4~alkyl~ hydroxy(C2-C4)alkyleneamino, (Cl~
C3)alkoxyCOCH2N(CH3),amino(CI-C5)alkyl,morpholino,piperidyl, hydroxypiperidino, 4-oxopiperidino, piperazino, 4-oxopiperidino ethylene ketal, ~l-(C~-C3)alkylpiperazino, thiomorpholino, thiomorpholino 1-oxide, thiomorpholino 1,1-dioxide, N-(CI-C4) alkoxycarbonylpiperidyl, 4-(CI-C4)alkoxy-carbonylpiperazinoJ 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (Cl-C3)alkoxycarbonyl-(s~-pyrrolid-2-yl or 4- (Cl-c4) alkanoylpiperazino; Y is C=O, P(OCH3)=O or SO2; A is N~CH3), NH or O; m and p are independently selected from the integ~rs O and 1; M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C6-C1)cycloalkyl; Q is methyl or hydrogen; R2 is (C~ C5)alkyl, ~C~-C3)alkylthio(C~-C2)alkyl, (C~-C3)alkoxy(CI-C2)alkyl, benzyloxy(C~-C~)alkyl, benzyl, hydroxy(CI-C2)alkyl, carboxy(C~-C2)alkyl, guanido(Cl-C3)alkyl, (Cl-C3)alkylsulfinyl(CI-C2)alkyl, (Cl-C3) alkylsulfonyl(CI-C2)alkyl, 4-benzyloxycarbonylamino-butyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t-butoxycarbonylimidazol-4-ylmPthyl or carbamyl(C~-C2)alkyl; X is cyclohexyl, l-propyl or phenyl;
w is cH~ loco(cl-c3)alkyldi(cl-c2)alkylamino~ CHl~llllOCO(CI-C3) alkylpiperidino, CH\llllOH, C-O, CH _ N3, CHIIIIIIN3, CH~NH2, 20~a~
CH~ NH2, C(CH3)~0H, C(CH3)1111110H, CH1~ 0CO(C1-C2)alkyl or CH11~11)0CO(C1-C2)a~kylene CO2H; Z~ is CH20H or R-U-T where R is C=O, U is 0, NH, N(CH3), CH2 or a chemical bond linking R and T, T is (C1-C5)alkyl, hydroxy( C,-C4) alkyl, CONH-(C1-C4)alkyl, hydrogen, trifluoroethyl, (C6-C7)cycloalkyl, (C6-~)cycloalkylmethyl, phenyl, benzyl, amino(C2-Cs)alkyl, O-(C~-C2)alkyl hydroxylamino, morpholino, 4-(Cl-C2)alkylpiperazino or omega-di(C1-C2)alkylamino(C3-C5)alkyl; L is CH or N; R5 is imidazol-4-ylmethyl or (C2-C5)alkyl; and ~ is (C~-C4)alkoxy or (C~-C4~alkylamino with the provisos that when m is 0, p is 0;
when A is 0, Y is C=O; when T is CONH-(C~-C4)alkyl, U is NH, N(CH3) or CH2; and when T is (C2-C5)alkylamino, O-(C1-C2)alkyl hydroxylamino, morpholino or 4-(C1-C2)-alkylpiperazino, U is CH2 or a chemical bond linking R and T.
A preferred group of compounds are those of formula I, wherein Y is C=O, A is NH, Q is hydrogen, X is cyclohexyl, W is CH1IIOH, R is C=O, T is benzyl or (C1-C5)alkyl and m and p are each l. Especially preferred within this group are compounds where R1 is morpholino, M is phenyl, U is O and R2 is a n-propyl and T is i propyl, where R2 is CH3SCH2- and T is i~propyl, where ~2 is n-butyl and T i5 methyl, where R2 is HOCH2 and T is i-propyl, where R2 is CH30(CH2)2-and T is i-propyl, where R2 is CH3SCH2- and T is ben7.yl, where R2 is methyl and T is i-propyl1 where R2 is n-butyl and T is i-propyl, where R2 i5 CH30CH2- and T is i-propyl and where R2 is CH3CH2~CH2- and T is i-propyl. Also especially preferred within this group are compounds M is phenyl, U is 0, T is i-propyl, R2 is CH3SCH2- and R1 is pyrrolidyl, 4-pyridyl, piperazino, 4-oxopiperidino or 4-hydroxypiperidino~ Also especially preferred within this group are those compounds where R~ is morpholino, M is phenyl, U is a chemical bond linking R and T and R2 is n-butyl and T is CH2CH(CH3~2, and where R2 is CH3SCH2 and T is CH2CH(CH3)2. Also especially preferred within this group are compounds where R1 is morpholino, U is O and where M is 2-thienylt R2 is CH3SCH2 and T is i-propyl, where M i5 4-hydroxyphenyl, R2 is CH3SCH2 and Q~9 T is i-propyl and where M is 4-methoxyphenyl, R2 is n-butyl and T is methyl. Also especially preferred in this group is the compound where Rl is morpholino, M is phenyl, R2 is a butyl, U is NH and T is methyl.
A preferred group of compounds are those of formula I
where M is phenyl, U is a chemical bond linking R and T, T is (Cl-C5)alkyl and R is C=O.
The present invention also includes a pharmaceutical composition for use in treating ocular hypertension or glaucoma in an eye, comprising an effective intraocular hypertension reduc-ing amount of at least one compound of formula I and II as defined above, and a pharmaceutically acceptable carrier. The composi-tion is isotonic with tears when it is based on an aqueous carrier.
As previously indicated, the present invention may utilize pharmaceutically acceptable saits of the biologically active compounds. Such salts are those which are non-toxic at the dosages administered. Since compounds of the invention may contain basic groups, acid addition salts are possible. Pharma-ceutically acceptable acid addition salts include e.g. the hydro-chloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate and saccharate salts.
Deta~led Description of the Invention The compounds of formulae I and II and their pharmaceutically acceptable salts (hereinafter also referred to as ~0~ 49 - 4a - 64680-610 active compounds) are described in Uni.ted States Patent Nos.
4,814,342 and 4~935,405~
The property of reducing intraocular pressure in animals, including man, can be tested using the procedure described by A~ M. Tinjum, _cta Opthalmologica, 50, 677 (1972).
The procedure involves using New Zealand rabbits weighing
v TREATMENT OF OCULAR HYPERTENSION AND GLAUCOMA
0 1ie ~ ~f th~ Irve~tion The present invention relates to a method of treating patients suffering from glaucoma or ocular hypertension using nor-statine and nor-cyclostatine polypeptides.
B kqround of the Invention Glaucoma is a disease which ePfects the lives of many people. This eye disorder is caused by an increase in intraocular pressure, also known as ocular hypertension or glaucoma. Chronic glaucoma manifests itself through a gradual and progressive los~ of visual fields. Without treatment, such condition ultimately results in blindness.
Treatment has typically involved the topical application of agonists or antagonists of autonomic neuroeffectors, such as pilocarpine or timolol, or the systematic administration of carbonic anhydrase inhibitors. Failure of such topical methods leaves surgery as the only alternative. As a result, newer and safer drugs causing fewer side effects are constantly being investigated~
The compounds used in the present invention are known to have a renin inhibitory effect and thus be useful in treating certain forms of hypertension and congestive heart failure as disclosed in United States Patent Nos. 4,814,342 and 4,935,405. W. J. Giardina, et al, Pharmacol., 31, 124 30 (1989); H. H. 5tein, et al, Pharmacol., 31, 124 (1989); and European Patent Publication No. 0364804 refer to the use of certain renin-inhibitory compounds in the treatment of glaucoma.
Summary of the Invention The present invention relates to a method for treating glaucoma or ocular hypertension comprising administering an effective intraocular hypertension reducing amount of at least one compound of the formula ~2--Z ~C / y ~ N~
0 ~2 and ~13 N C 1~ C O R 6 H ll = H g Rs OH
or a pharmaceutically acceptable salt thereof, wherein Z is Rl-(Y)m-(A3p, where Rl is (Cl-C6)alkyl, amino, (Cl-C4)alkoxy, (Cl-C4)alkylamino, (Cl-C3)alkoxy (C2 C4) alkylenPamino~
15 CarbOXy(Cl-C4~alkyl~ hydroxy(C2-C4)alkyleneamino, (Cl~
C3)alkoxyCOCH2N(CH3),amino(CI-C5)alkyl,morpholino,piperidyl, hydroxypiperidino, 4-oxopiperidino, piperazino, 4-oxopiperidino ethylene ketal, ~l-(C~-C3)alkylpiperazino, thiomorpholino, thiomorpholino 1-oxide, thiomorpholino 1,1-dioxide, N-(CI-C4) alkoxycarbonylpiperidyl, 4-(CI-C4)alkoxy-carbonylpiperazinoJ 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (Cl-C3)alkoxycarbonyl-(s~-pyrrolid-2-yl or 4- (Cl-c4) alkanoylpiperazino; Y is C=O, P(OCH3)=O or SO2; A is N~CH3), NH or O; m and p are independently selected from the integ~rs O and 1; M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C6-C1)cycloalkyl; Q is methyl or hydrogen; R2 is (C~ C5)alkyl, ~C~-C3)alkylthio(C~-C2)alkyl, (C~-C3)alkoxy(CI-C2)alkyl, benzyloxy(C~-C~)alkyl, benzyl, hydroxy(CI-C2)alkyl, carboxy(C~-C2)alkyl, guanido(Cl-C3)alkyl, (Cl-C3)alkylsulfinyl(CI-C2)alkyl, (Cl-C3) alkylsulfonyl(CI-C2)alkyl, 4-benzyloxycarbonylamino-butyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t-butoxycarbonylimidazol-4-ylmPthyl or carbamyl(C~-C2)alkyl; X is cyclohexyl, l-propyl or phenyl;
w is cH~ loco(cl-c3)alkyldi(cl-c2)alkylamino~ CHl~llllOCO(CI-C3) alkylpiperidino, CH\llllOH, C-O, CH _ N3, CHIIIIIIN3, CH~NH2, 20~a~
CH~ NH2, C(CH3)~0H, C(CH3)1111110H, CH1~ 0CO(C1-C2)alkyl or CH11~11)0CO(C1-C2)a~kylene CO2H; Z~ is CH20H or R-U-T where R is C=O, U is 0, NH, N(CH3), CH2 or a chemical bond linking R and T, T is (C1-C5)alkyl, hydroxy( C,-C4) alkyl, CONH-(C1-C4)alkyl, hydrogen, trifluoroethyl, (C6-C7)cycloalkyl, (C6-~)cycloalkylmethyl, phenyl, benzyl, amino(C2-Cs)alkyl, O-(C~-C2)alkyl hydroxylamino, morpholino, 4-(Cl-C2)alkylpiperazino or omega-di(C1-C2)alkylamino(C3-C5)alkyl; L is CH or N; R5 is imidazol-4-ylmethyl or (C2-C5)alkyl; and ~ is (C~-C4)alkoxy or (C~-C4~alkylamino with the provisos that when m is 0, p is 0;
when A is 0, Y is C=O; when T is CONH-(C~-C4)alkyl, U is NH, N(CH3) or CH2; and when T is (C2-C5)alkylamino, O-(C1-C2)alkyl hydroxylamino, morpholino or 4-(C1-C2)-alkylpiperazino, U is CH2 or a chemical bond linking R and T.
A preferred group of compounds are those of formula I, wherein Y is C=O, A is NH, Q is hydrogen, X is cyclohexyl, W is CH1IIOH, R is C=O, T is benzyl or (C1-C5)alkyl and m and p are each l. Especially preferred within this group are compounds where R1 is morpholino, M is phenyl, U is O and R2 is a n-propyl and T is i propyl, where R2 is CH3SCH2- and T is i~propyl, where ~2 is n-butyl and T i5 methyl, where R2 is HOCH2 and T is i-propyl, where R2 is CH30(CH2)2-and T is i-propyl, where R2 is CH3SCH2- and T is ben7.yl, where R2 is methyl and T is i-propyl1 where R2 is n-butyl and T is i-propyl, where R2 i5 CH30CH2- and T is i-propyl and where R2 is CH3CH2~CH2- and T is i-propyl. Also especially preferred within this group are compounds M is phenyl, U is 0, T is i-propyl, R2 is CH3SCH2- and R1 is pyrrolidyl, 4-pyridyl, piperazino, 4-oxopiperidino or 4-hydroxypiperidino~ Also especially preferred within this group are those compounds where R~ is morpholino, M is phenyl, U is a chemical bond linking R and T and R2 is n-butyl and T is CH2CH(CH3~2, and where R2 is CH3SCH2 and T is CH2CH(CH3)2. Also especially preferred within this group are compounds where R1 is morpholino, U is O and where M is 2-thienylt R2 is CH3SCH2 and T is i-propyl, where M i5 4-hydroxyphenyl, R2 is CH3SCH2 and Q~9 T is i-propyl and where M is 4-methoxyphenyl, R2 is n-butyl and T is methyl. Also especially preferred in this group is the compound where Rl is morpholino, M is phenyl, R2 is a butyl, U is NH and T is methyl.
A preferred group of compounds are those of formula I
where M is phenyl, U is a chemical bond linking R and T, T is (Cl-C5)alkyl and R is C=O.
The present invention also includes a pharmaceutical composition for use in treating ocular hypertension or glaucoma in an eye, comprising an effective intraocular hypertension reduc-ing amount of at least one compound of formula I and II as defined above, and a pharmaceutically acceptable carrier. The composi-tion is isotonic with tears when it is based on an aqueous carrier.
As previously indicated, the present invention may utilize pharmaceutically acceptable saits of the biologically active compounds. Such salts are those which are non-toxic at the dosages administered. Since compounds of the invention may contain basic groups, acid addition salts are possible. Pharma-ceutically acceptable acid addition salts include e.g. the hydro-chloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate and saccharate salts.
Deta~led Description of the Invention The compounds of formulae I and II and their pharmaceutically acceptable salts (hereinafter also referred to as ~0~ 49 - 4a - 64680-610 active compounds) are described in Uni.ted States Patent Nos.
4,814,342 and 4~935,405~
The property of reducing intraocular pressure in animals, including man, can be tested using the procedure described by A~ M. Tinjum, _cta Opthalmologica, 50, 677 (1972).
The procedure involves using New Zealand rabbits weighing
2.0-2.5 kg and placing the rabbits in a restraining device during the testing pexiod. Measurement of ~5--intraocular pressure (IOP) is made on the eyes of the rabbits with an applamatic tonometer. For each animal, IOP
control measurements are made three times before application of test compounds or vehicle are applied, each time separated by thirty minutes.
After the control measurements have been completed, an amount of test compound or vehicle is applied into the conjunctival sac of one eye of the rabbit. IOP measurements are then taken of that eye and the untreated contralateral eye periodically, e.g. 5, 15t 30, 60, 90, 120, and 150 minutes, after treatment. A reduction in IOP demonstrates intraocular antihypertensive activity.
The present invention is practiced by applying one or more of the nor-statine and nor~cyclostatine compounds topically to the eye in either aqueous solutions, suspensions, or ointments. Typically, these compositions contain approximately 0.001% to 1% of the active compounds and would be applied about twice a day. The amount of the ointment or suspension to be applied to the eye would typically be about 0.1 ml.
The active compounds can be administered using a variety of formulations, including, but not limited to, aqueous solutions, suspensions, and ointments. An aqueous solution for use in the method of the present invention would contain about 0.001% to 1% of active compound in water. The solubility of active compound in the a~ueous solution will depend upon the specific active compound used as well as other additives present. A liquid suspension for use in the method of the present invention would contain approximately 0.1 to 10% of active compound in water. Both the aqueous solution and liquid suspension would be buffered to between pH 4~0 and pH 8.0 using, for example, citrate or phosphate buffer. A suitable preservative, for either solution or suspension such as benzalkium chloride, (about 0.001%) or sorbic acid (about 0.1%) should also be present.
Both solution and suspension should be made isotonic with tears using, for example, sodium chloride. A suitable 2 ~ 0 ~ ~
suspending agent would also be neGessary for the liquid suspension, such as cellulose (about 0.2% to about 2~), polyvinyl alcohol (about 0.1% to about 1%), or polyacrylic acid tabout 0.1% to about 0.5%), preferably cellulo~e.
An ointment for use in the method of the present invention would contain 0.1 to 10% of active compound.
Active compound is suspended in an inert oil-based vehicle, such as, for example, mineral oil or petroleum oil. Th~
ointment should also contain a suitable preservatives, such as those used in the water suspension illustrated above.
A very practical form of the pharmaceutical composition is an eye drop containing the aqueous solution or suspension mentioned above.
The pharmaceutical composition may be put in a commercial package for practical use. The package may carry instructions that the composition can be used for treating glaucoma or ocular hypertension.
control measurements are made three times before application of test compounds or vehicle are applied, each time separated by thirty minutes.
After the control measurements have been completed, an amount of test compound or vehicle is applied into the conjunctival sac of one eye of the rabbit. IOP measurements are then taken of that eye and the untreated contralateral eye periodically, e.g. 5, 15t 30, 60, 90, 120, and 150 minutes, after treatment. A reduction in IOP demonstrates intraocular antihypertensive activity.
The present invention is practiced by applying one or more of the nor-statine and nor~cyclostatine compounds topically to the eye in either aqueous solutions, suspensions, or ointments. Typically, these compositions contain approximately 0.001% to 1% of the active compounds and would be applied about twice a day. The amount of the ointment or suspension to be applied to the eye would typically be about 0.1 ml.
The active compounds can be administered using a variety of formulations, including, but not limited to, aqueous solutions, suspensions, and ointments. An aqueous solution for use in the method of the present invention would contain about 0.001% to 1% of active compound in water. The solubility of active compound in the a~ueous solution will depend upon the specific active compound used as well as other additives present. A liquid suspension for use in the method of the present invention would contain approximately 0.1 to 10% of active compound in water. Both the aqueous solution and liquid suspension would be buffered to between pH 4~0 and pH 8.0 using, for example, citrate or phosphate buffer. A suitable preservative, for either solution or suspension such as benzalkium chloride, (about 0.001%) or sorbic acid (about 0.1%) should also be present.
Both solution and suspension should be made isotonic with tears using, for example, sodium chloride. A suitable 2 ~ 0 ~ ~
suspending agent would also be neGessary for the liquid suspension, such as cellulose (about 0.2% to about 2~), polyvinyl alcohol (about 0.1% to about 1%), or polyacrylic acid tabout 0.1% to about 0.5%), preferably cellulo~e.
An ointment for use in the method of the present invention would contain 0.1 to 10% of active compound.
Active compound is suspended in an inert oil-based vehicle, such as, for example, mineral oil or petroleum oil. Th~
ointment should also contain a suitable preservatives, such as those used in the water suspension illustrated above.
A very practical form of the pharmaceutical composition is an eye drop containing the aqueous solution or suspension mentioned above.
The pharmaceutical composition may be put in a commercial package for practical use. The package may carry instructions that the composition can be used for treating glaucoma or ocular hypertension.
Claims (30)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition for treating ocular hypertension or glaucoma in an eye, the said composition being in a form adapted to be topically administered to the surface of the eye, being isotonic with tears when the composition is based on water and comprising an effective intraocular hypertension reduc-ing amount of at least one compound of the formula:
and (wherein:
Z is R1-(Y)m-(A)p, [where R1 is (C1-C6)alkyl, amino, (C1-C4)alkoxy, (C1-C4)alkylamino, (C1-C3)alkoxy(C2-C4)alkylamino, carboxy(C1-C4)alkyl, hydroxy (C2-C4)alkylamino, (C1-C3)alkoxy-COCH2N(CH3), amino(C1-C5)alkyl, morpholino, piperidyl, hydroxy-piperidino, 4-oxopiperidino, piperazino, 4-oxopipieridino ethy-lene ketal, 4-(C1-C3)alkylpiperazino, thiomorpholino, thiomor-pholino 1-oxide, thiomorpholino 1,1-dioxide, N-(C1-C4)alkoxycar-bonylpiperidyl, 4-(C1-C4)alkoxycarbonylpiperazino, 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (C1-C3)alkoxycarbonyl-(s)-pyrrolid-2-yl or 4-(C1-C4)alkanoylpiperazino; Y is C=O, P(OCH3)=O, or SO2; A is N(CH3), NH or O; m and p are independently selected from the integers O and l];
M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C6-C7)cycloalkyl;
Q is methyl or hydrogen;
R2 is (C1-C5)alkyl, (C1-C3)alkylthio(C1-C2)alkyl, (C1-C3)alkoxy(C1-C2)alkyl, benzyloxy(C1-C2)alkyl, benzyl, hydroxy (C1-C2)alkyl, carboxy(C1-C2)alkyl, guanido(C1-C3)alkyl, (C1-C3) alkylsulfinyl(C1-C2)alkyl, (C1 C3)alkylsulfonyl(C1-C2)alkyl, 4-benzyloxycarbonylaminobutyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t-butoxycarbonylimidazol-4-ylmethyl or carbamyl(C1-C2)alkyl;
X is cyclohexyl, 1-propyl or phenyl;
W is di(C1-C2)alkylamino(C1-C3)alkyl-OOC-CH, piperidino(C1-C3)alkyl OOC-CH, HO-CH, O=C, N3-CH, N3 CH, H2N-CH, H2N CH, HO-C(CH3), HO C(CH3), (C1-C2)alkyl-OOC-CH
or HOOC(C1-C2)alkyl-OOC-CH;
Z1 is CH2OH or R-U-T [where R is C=O, U is O, NH, N(CH3), CH2 or a chemical bond linking R and T; T is (C1-C5)alkyl hydroxy(C1-C4)alkyl, CONH(C1-C4)alkyl, hydrogen, trifluoroethyl, (C6-C7)cycloalkyl, (C6-C7)cycloalkylmethyl, phenyl, benzyl, amino(C2-C5)alkyl, O-(C1-C2)alkyl-hydroxylamino, morpholino, 4-(C1-C2)alkylpiperazino or omega-di(C1-C2)alkylamino(C3-C5)alkyl;
L is CH or N;
R5 is imidazol-4-ylmethyl or (C2-C5)alkyl; and R6 is (C1-Ca)alkoxy or (C1-C4)alkylamino, with the provisos that when m is O, p is O; when A is O, Y is C=O; when T is CONH-(C1-C4)alkyl, U is NH, N(CH3) or CH2;
and when T is (C2-C5)alkylaminol O-(C1-C2)alkyl-hydroxylamino, morpholino or 4-(C1-C2)alkylpiperazino, U is CH2 or a chemical bond linking R and T), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
and (wherein:
Z is R1-(Y)m-(A)p, [where R1 is (C1-C6)alkyl, amino, (C1-C4)alkoxy, (C1-C4)alkylamino, (C1-C3)alkoxy(C2-C4)alkylamino, carboxy(C1-C4)alkyl, hydroxy (C2-C4)alkylamino, (C1-C3)alkoxy-COCH2N(CH3), amino(C1-C5)alkyl, morpholino, piperidyl, hydroxy-piperidino, 4-oxopiperidino, piperazino, 4-oxopipieridino ethy-lene ketal, 4-(C1-C3)alkylpiperazino, thiomorpholino, thiomor-pholino 1-oxide, thiomorpholino 1,1-dioxide, N-(C1-C4)alkoxycar-bonylpiperidyl, 4-(C1-C4)alkoxycarbonylpiperazino, 3-oxomorpholino, 3,5-dioxomorpholino, hydroxypyridyl, pyridyl, (s)-pyrrolid-2-yl, N-t-butoxycarbonyl-(s)-pyrrolid-2-yl, (C1-C3)alkoxycarbonyl-(s)-pyrrolid-2-yl or 4-(C1-C4)alkanoylpiperazino; Y is C=O, P(OCH3)=O, or SO2; A is N(CH3), NH or O; m and p are independently selected from the integers O and l];
M is phenyl, benzyl, naphthyl, thienyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or (C6-C7)cycloalkyl;
Q is methyl or hydrogen;
R2 is (C1-C5)alkyl, (C1-C3)alkylthio(C1-C2)alkyl, (C1-C3)alkoxy(C1-C2)alkyl, benzyloxy(C1-C2)alkyl, benzyl, hydroxy (C1-C2)alkyl, carboxy(C1-C2)alkyl, guanido(C1-C3)alkyl, (C1-C3) alkylsulfinyl(C1-C2)alkyl, (C1 C3)alkylsulfonyl(C1-C2)alkyl, 4-benzyloxycarbonylaminobutyl, 4-aminobutyl, imidazol-4-ylmethyl, N-t-butoxycarbonylimidazol-4-ylmethyl or carbamyl(C1-C2)alkyl;
X is cyclohexyl, 1-propyl or phenyl;
W is di(C1-C2)alkylamino(C1-C3)alkyl-OOC-CH, piperidino(C1-C3)alkyl OOC-CH, HO-CH, O=C, N3-CH, N3 CH, H2N-CH, H2N CH, HO-C(CH3), HO C(CH3), (C1-C2)alkyl-OOC-CH
or HOOC(C1-C2)alkyl-OOC-CH;
Z1 is CH2OH or R-U-T [where R is C=O, U is O, NH, N(CH3), CH2 or a chemical bond linking R and T; T is (C1-C5)alkyl hydroxy(C1-C4)alkyl, CONH(C1-C4)alkyl, hydrogen, trifluoroethyl, (C6-C7)cycloalkyl, (C6-C7)cycloalkylmethyl, phenyl, benzyl, amino(C2-C5)alkyl, O-(C1-C2)alkyl-hydroxylamino, morpholino, 4-(C1-C2)alkylpiperazino or omega-di(C1-C2)alkylamino(C3-C5)alkyl;
L is CH or N;
R5 is imidazol-4-ylmethyl or (C2-C5)alkyl; and R6 is (C1-Ca)alkoxy or (C1-C4)alkylamino, with the provisos that when m is O, p is O; when A is O, Y is C=O; when T is CONH-(C1-C4)alkyl, U is NH, N(CH3) or CH2;
and when T is (C2-C5)alkylaminol O-(C1-C2)alkyl-hydroxylamino, morpholino or 4-(C1-C2)alkylpiperazino, U is CH2 or a chemical bond linking R and T), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
2. The composition of claim 1, which contains a compound of formula I, wherein Y is C=O, A is NH, Q is hydrogen, X is cyclohexyl, W is CH OH, R is C=O, T is benzyl or (C1-C5)alkyl and m and p are each 1.
3. The composition of claim 2, wherein R1 is morpholino, M is 2-thienyl, R2 is CH3SCH2-, U is O and T is i-propyl.
4. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is n-propyl, U is O and T is i-propyl.
5. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is CH3SCH2-, U is O and T is i-propyl.
6. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is n-butyl, U is O and T is methyl.
7. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is n-butyl, U is NH and T is methyl.
8. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is n-butyl, U is a chemical bond linking R and T
and T is CH2CH(CH3)2.
and T is CH2CH(CH3)2.
9. The composition of claim 2, wherein R1 is 2-pyrrolidyl, M is phenyl, R2 is CH3SCH2-, U is O and T is i-propyl.
10. The composition of claim 2, wherein R1 is 4-pyridyl, M is phenyl, R2 is CH3SCH2-, U is O and T is i-propyl.
11. The composition of claim 2, wherein R1 is piperazino, M is phenyl, R2 is CH3SCH2- , U is O and T is i-propyl.
12 The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is CH3SCH2-, U is a chemical bond linking R and T
and T is -CH2CH(CH3)2.
and T is -CH2CH(CH3)2.
13. The composition of claim 2, wherein R1 is 4-hydroxy-piperidino, M is phenyl, R2 is CH3SCH2-, U is O and T is i-propyl.
14. The composition of claim 2, wherein Rl is morpholino, M is phenyl, R2 is HOCH2-, U is O and T is i-propyl.
15. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is CH30(CH2)2-, U is O and T is i-propyl.
16. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is CH3SCH2-, U is O and T is benzyl.
17. The composition of claim 2, wherein R1 is morpholino, M is 4-hydroxyphenyl, R2 is CH3SCH2-, U is O and T is i-propyl.
18. The composition of claim 2, wherein R1 is morpholino, M is 4-methoxyphenyl, R2 is n-butyl, U is O and T is methyl.
l9. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is methyl, U is O and T is i-propyl.
20. The composition of claim 2, wherein R1 is 4-oxo-piperidino, M is phenyl, R2 is CH3SCH2-, U is O and T is i-propyl.
21. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is n-butyl, U is O and T is i-propyl.
22. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is CH3OCH2-, U is O and T is i-propyl.
23. The composition of claim 2, wherein R1 is morpholino, M is phenyl, R2 is CH3CH2OCH2-, U is O and T is i-propyl.
24. A composition of claim 1, which contains a compound of formula I, wherein M is phenyl, U is a chemical bond linking R and T, T is (C1-C5)alkyl and R is C=O.
25. A composition of any one of claims 1 to 24, which is in the form of an eye drop isotonic with tears.
26. A composition of claim 25, which is an aqueous solution containing 0.001 to 1% by weight of the compound or salt dissolved in water which is buffered within a pH range between 4.0 and 8.0 and also contains a preservative.
27. A composition of claim 25, which is an aqueous sus-pension containing 0.1 to lO% by weight of the compound or salt suspended in water which is buffered within a pH range between 4.0 and 8.0 and also contains a preservative and a suspending agent.
28. A composition of any one of claims l to 24, which is in the form of an ointment containing 0.1 to lO% by weight of the compound or salt suspended in an inert oil-based vehicle and also containing a preservative.
29. A commercial package which contains the composition of any one of claims 1 to 24 and carries instructions that the composition can be used for treating glaucoma or ocular hyper-tension.
30. A use of a compound of the formula I or II as defined in claim l or a pharmaceutically acceptable salt thereof for treating glaucoma or ocular hypertension.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57463590A | 1990-08-29 | 1990-08-29 | |
| US574,635 | 1990-08-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2050049A1 true CA2050049A1 (en) | 1992-03-01 |
Family
ID=24296958
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002050049A Abandoned CA2050049A1 (en) | 1990-08-29 | 1991-08-27 | Nor-statine and nor-cyclostatine polypeptides in the treatment of ocular hypertension and glaucoma |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0473337A3 (en) |
| JP (1) | JPH04243835A (en) |
| CA (1) | CA2050049A1 (en) |
| IE (1) | IE913021A1 (en) |
| PT (1) | PT98782A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE404189T1 (en) * | 2004-04-26 | 2008-08-15 | Alcon Inc | STATINS FOR THE TREATMENT OF OCCULAR HYPERTENSION AND GLAUCOMA |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4906613A (en) * | 1985-11-05 | 1990-03-06 | Schering Corporation | Antiglaucoma compositions and methods |
| US4814342A (en) * | 1986-10-31 | 1989-03-21 | Pfizer Inc. | Nor-statine and nor-cyclostatine polypeptides |
| MY103189A (en) * | 1986-10-31 | 1993-05-29 | Pfizer | Nor-statine and nor-cyclostatine polypeptides |
| US4927807A (en) * | 1987-10-06 | 1990-05-22 | Abbott Laboratories | Glaucoma treatment |
| GB8728560D0 (en) * | 1987-12-07 | 1988-01-13 | Glaxo Group Ltd | Chemical compounds |
| IL91780A (en) * | 1988-10-04 | 1995-08-31 | Abbott Lab | Renin inhibiting hexanoic acid amide derivatives, process for their preparation and pharmaceutical compositions containing them |
-
1991
- 1991-07-30 JP JP3190097A patent/JPH04243835A/en active Pending
- 1991-08-15 EP EP19910307545 patent/EP0473337A3/en not_active Withdrawn
- 1991-08-27 PT PT98782A patent/PT98782A/en not_active Application Discontinuation
- 1991-08-27 CA CA002050049A patent/CA2050049A1/en not_active Abandoned
- 1991-08-28 IE IE302191A patent/IE913021A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE913021A1 (en) | 1992-03-11 |
| EP0473337A2 (en) | 1992-03-04 |
| PT98782A (en) | 1993-10-29 |
| EP0473337A3 (en) | 1992-05-27 |
| JPH04243835A (en) | 1992-08-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |